Development of specific antiviral agents is an urgent unmet need for SARS-coronavirus 2 (SARS-CoV-2) infection. This study focuses on host proteases that proteolytically activate the SARS-CoV-2 spike ...protein, critical for its fusion after binding to angiotensin-converting enzyme 2 (ACE2), as antiviral targets. We first validate cleavage at a putative furin substrate motif at SARS-CoV-2 spikes by expressing it in VeroE6 cells and find prominent syncytium formation. Cleavage and the syncytium are abolished by treatment with the furin inhibitors decanoyl-RVKR-chloromethylketone (CMK) and naphthofluorescein, but not by the transmembrane protease serine 2 (TMPRSS2) inhibitor camostat. CMK and naphthofluorescein show antiviral effects on SARS-CoV-2-infected cells by decreasing virus production and cytopathic effects. Further analysis reveals that, similar to camostat, CMK blocks virus entry, but it further suppresses cleavage of spikes and the syncytium. Naphthofluorescein acts primarily by suppressing viral RNA transcription. Therefore, furin inhibitors may be promising antiviral agents for prevention and treatment of SARS-CoV-2 infection.
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•The furin cleavage site in the SARS-CoV-2 spike protein mediates syncytium formation•The SARS-CoV-2 spike-mediated syncytium is suppressed by specific furin inhibitors•Furin inhibitors block SARS-CoV-2 virus entry and virus replication•Furin inhibitors are potential antiviral agents for SARS-CoV-2 infection and pathogenesis
Development of effective antiviral agents is an urgent unmet need for SARS-CoV-2 infection. Cheng et al. find that cleavage of the furin substrate site in the viral spike protein is critical for virus production and cytopathic effects. Two inhibitors targeting furin are potential antiviral agents to control SARS-CoV-2 infection and pathogenesis.
We report the results of ALMA observations of a protoplanetary disk surrounding the Herbig Ae star AB Aurigae. We obtained high-resolution (0 1; 14 au) images in 12CO J = 2 − 1 emission and in the ...dust continuum at the wavelength of 1.3 mm. The continuum emission is detected at the center and at the ring with a radius (r) of ∼120 au. The CO emission is dominated by two prominent spirals within the dust ring. These spirals are trailing and appear to be about 4 times brighter than their surrounding medium. Their kinematics is consistent with Keplerian rotation at an inclination of 23°. The apparent two-arm-spiral pattern is best explained by tidal disturbances created by an unseen companion located at r of 60-80 au, with dust confined in the pressure bumps created outside this companion orbit. An additional companion at r of 30 au, coinciding with the peak CO brightness and a large pitch angle of the spiral, would help to explain the overall emptiness of the cavity. Alternative mechanisms to excite the spirals are discussed. The origin of the large pitch angle detected here remains puzzling.
Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative ...strategies for disease modelling, drug discovery and regenerative medicine. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.
Abstract
Utilizing the Atacama Large Millimeter/submillimeter Array, we present CS line maps in five rotational lines (
J
u
= 7, 5, 4, 3, 2) toward the circumnuclear disk (CND) and streamers of the ...Galactic center. Our primary goal is to resolve the compact structures within the CND and the streamers, in order to understand the stability conditions of molecular cores in the vicinity of the supermassive black hole (SMBH) Sgr A*. Our data provide the first homogeneous high-resolution (1.″3 = 0.05 pc) observations aiming at resolving density and temperature structures. The CS clouds have sizes of 0.05–0.2 pc with a broad range of velocity dispersion (
σ
FWHM
= 5–40 km s
−1
). The CS clouds are a mixture of warm (
T
k
≥ 50–500 K,
n
H
2
= 10
3
–10
5
cm
−3
) and cold gas (
T
k
≤ 50 K,
n
H
2
= 10
6
–10
8
cm
−3
). A stability analysis based on the unmagnetized virial theorem including tidal force shows that
84
−
37
+
16
%
of the total gas mass is tidally stable, which accounts for the majority of gas mass. Turbulence dominates the internal energy and thereby sets the threshold densities 10–100 times higher than the tidal limit at distance ≥1.5 pc to Sgr A*, and therefore it inhibits the clouds from collapsing to form stars near the SMBH. However, within the central 1 pc, the tidal force overrides turbulence and the threshold densities for a gravitational collapse quickly grow to ≥ 10
8
cm
−3
.
Background
Nutritional counseling is frequently overlooked in cancer patients with normal nutritional status. This study aimed to evaluate the impact of nutritional counseling in head and neck cancer ...(HNC) patients with normal nutritional status prior to concurrent chemoradiotherapy (CCRT).
Methods
A total of 243 patients with pretreatment normal nutritional status and locally advanced HNC receiving concurrent chemoradiotherapy (CCRT) at three medical centers were enrolled. All patients were retrospectively allocated into the early (≤ 2 weeks,
n
= 105, 43.2%), late (> 2 weeks,
n
= 102, 42.0%), and no nutritional counseling groups (
n
= 36, 14.8%) according to the time interval between the date of CCRT initiation and the first date of nutritional counseling for comparison.
Results
The 1-year overall survival rates were 95.0%, 87.5%, and 81.3% in the early, late, and no nutritional counseling groups (
p
= 0.035), respectively. The median body weight changes at end of CCRT were − 4.8% (range, − 13.3 to 8.7%), − 5.6% (range, − 21.9 to 5.6%), and − 8.6% (range, − 20.3 to 2.4%) in patients in the early, late, and no nutritional counseling groups, respectively. The early termination of chemotherapy rates and the incompletion rates of planned radiotherapy were 1.9% and 1.9%, 2.9%, and 2.0%, 13.9%, and 19.4% in patients in the early, late, and no nutritional counseling groups, respectively.
Conclusions
Our findings strongly suggest that while some HNC patients may have pretreatment normal nutritional status, early nutritional counseling is nevertheless essential for the improvement of treatment tolerance and survival outcome.
Neutrophils play a critical role in acute and chronic inflammatory processes, including myocardial ischemia/reperfusion injury, sepsis, and adult respiratory distress syndrome. Binding of formyl ...peptide receptor 1 (FPR1) by N-formyl peptides can activate neutrophils and may represent a new therapeutic target in either sterile or septic inflammation. Propofol, a widely used i.v. anesthetic, has been shown to modulate immunoinflammatory responses. However, the mechanism of propofol remains to be established. In this study, we showed that propofol significantly reduced superoxide generation, elastase release, and chemotaxis in human neutrophils activated by fMLF. Propofol did not alter superoxide generation or elastase release in a cell-free system. Neither inhibitors of γ-aminobutyric acid receptors nor an inhibitor of protein kinase A reversed the inhibitory effects of propofol. In addition, propofol showed less inhibitory effects in non-FPR1-induced cell responses. The signaling pathways downstream from FPR1, involving calcium, AKT, and ERK1/2, were also competitively inhibited by propofol. These results show that propofol selectively and competitively inhibits the FPR1-induced human neutrophil activation. Consistent with the hypothesis, propofol inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analog of fMLF, to FPR1 in human neutrophils, differentiated THP-1 cells, and FPR1-transfected human embryonic kidney-293 cells. To our knowledge, our results identify, for the first time, a novel anti-inflammatory mechanism of propofol by competitively blocking FPR1 in human neutrophils. Considering the importance of N-formyl peptides in inflammatory processes, our data indicate that propofol may have therapeutic potential to attenuate neutrophil-mediated inflammatory diseases by blocking FPR1.
Abstract
We use molecular line data from the Atacama Large Millimeter/submillimeter Array, Submillimeter Array, James Clerk Maxwell Telescope, and NANTEN2 to study the multiscale (∼15–0.005 pc) ...velocity statistics in the massive star formation region NGC 6334. We find that the nonthermal motions revealed by the velocity dispersion function (VDF) stay supersonic over scales of several orders of magnitude. The multiscale nonthermal motions revealed by different instruments do not follow the same continuous power law, which is because the massive star formation activities near central young stellar objects have increased the nonthermal motions in small-scale and high-density regions. The magnitudes of VDFs vary in different gas materials at the same scale, where the infrared dark clump N6334S in an early evolutionary stage shows a lower level of nonthermal motions than other more evolved clumps due to its more quiescent star formation activity. We find possible signs of small-scale-driven (e.g., by gravitational accretion or outflows) supersonic turbulence in clump N6334IV with a three-point VDF analysis. Our results clearly show that the scaling relation of velocity fields in NGC 6334 deviates from a continuous and universal turbulence cascade due to massive star formation activities.
The interaction between a supermassive black hole (SMBH) and the surrounding material is of primary importance in modern astrophysics. The detection of the molecular 2 pc circumnuclear disk (CND) ...immediately around the Milky Way SMBH, SgrA*, provides a unique opportunity to study SMBH accretion at subparsec scales. Our new wide-field CS(J = 2 − 1) map toward the Galactic center (GC) reveals multiple dense molecular streamers that originated from the ambient clouds 20 pc further out, and that are connected to the central 2 pc of the CND. These dense gas streamers appear to carry gas directly toward the nuclear region and might be captured by the central potential. Our phase-plot analysis indicates that these streamers show a signature of rotation and inward radial motion with progressively higher velocities as the gas approaches the CND and finally ends up corotating with the CND. Our results might suggest a possible mechanism of gas feeding the CND from 20 pc around 2 pc in the GC. In this paper, we discuss the morphology and the kinematics of these streamers. As the nearest observable Galactic nucleus, this feeding process may have implications for understanding the processes in extragalactic nuclei.
We present the first ALMA dust polarization observations toward the high-mass star-forming regions W51 e2, e8, and W51 North in Band 6 (230 GHz) with a resolution of about (∼5 mpc). Polarized ...emission in all three sources is clearly detected and resolved. Measured relative polarization levels are between 0.1% and 10%. While the absolute polarization shows complicated structures, the relative polarization displays the typical anticorrelation with Stokes I, although with a large scatter. Inferred magnetic (B) field morphologies are organized and connected. Detailed substructures are resolved, revealing new features such as comet-shaped B-field morphologies in satellite cores, symmetrically converging B-field zones, and possibly streamlined morphologies. The local B-field dispersion shows some anticorrelation with the relative polarization. Moreover, the lowest polarization percentages together with largest dispersions coincide with B-field convergence zones. We put forward , where is the measurable angle between a local B-field orientation and local gravity, as a measure of how effectively the B field can oppose gravity. Maps of for all three sources show organized structures that suggest a locally varying role of the B field, with some regions where gravity can largely act unaffectedly, possibly in a network of narrow magnetic channels, and other regions where the B field can work maximally against gravity.
Multiple interplays between viral and host factors are involved in influenza virus replication and pathogenesis. Several small RNAs have recently emerged as important regulators of host response to ...viral infections. The aim of this study was to characterize the functional role of hsa-miR-1975, a Y5 RNA-derived small RNA, in defending influenza virus and delineate the mechanisms.
We performed high throughput sequencing of small RNAs in influenza virus-infected cells to identify up- or down- regulated small RNA species. The expression of the most abundant RNA species (hsa-miR-1975) was validated by stem-loop reverse transcription-polymerase chain reaction (RT-PCR). Antiviral effects of hsa-miR-1975 were confirmed by Western Blot, RT-PCR and plaque assay. In vitro perturbation of hsa-miR-1975 combined with exosomes isolation was used to elucidate the role and mechanism of hsa-miR-1975 in the context of antiviral immunity.
Small RNA sequencing revealed that hsa-miR-1975 was the most up-regulated small RNA in influenza virus-infected cells. The amount of intracellular hsa-miR-1975 increased in the late stage of the influenza virus replication cycle. The increased hsa-miR-1975 was at least partially derived from degradation of Y5RNA as a result of cellular apoptosis. Unexpectedly, hsa-miR-1975 mimics inhibited influenza virus replication while hsa-miR-1975 sponges enhanced the virus replication. Moreover, hsa-miR-1975 was secreted in exosomes and taken up by the neighboring cells to induce interferon expression.
Our findings unravel a critical role of Y-class small RNA in host's defense against influenza virus infection and reveal its antiviral mechanism through exosome delivery. This may provide a new candidate for targeting influenza virus.
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